ES2285775T3 - SUBSTITUTED HETEROCICLIC COMPOUNDS, THE PREPARATION PROCEDURE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. - Google Patents

Abstract

Compound of formula (I): (See formula) where: * R 1 represents an OR 4 group in which R 4 represents a hydrogen atom, a linear or branched (C1-C6) alkyl group substituted or not, alkenyl (C2) -C6) linear or branched substituted or not, linear or branched (C2-C6) alkynyl substituted or unbranched, aryl, aryl, linear or branched (C1-C6) alkyl, cycloalkyl (C3-C8) substituted or not or cycloalkyl (C3-C8) ) linear or branched (C1-C6) alkyl, substituted or not, * R 2 represents a hydrogen atom, or R 1 and R 2, located on two adjacent carbons form, together with the carbon atoms that carry them, a group phenyl or substituted phenyl, * X represents a CH or CH2 group, * Y represents an oxygen atom, * R 3 represents a hydrogen atom, a linear or branched aryl, aryl (C1-C6) alkyl or (C1-C6) alkyl ) linear or branched, * n is worth 0, 1, 2, 3, 4 or 5 when R 1 and R 2, located on two adjacent carbons, together with the carbon atoms that carry them, form a g rupo phenyl or substituted phenyl, or n equals 1, 2, 3, 4, or 5 when R 2 represents a hydrogen atom, * A represents: does a group NR 5 R 6.

Description

Heterocyclic substituted compounds, their preparation procedure and pharmaceutical compositions that they contain.

The invention relates to new derivatives substituted heterocyclics, to their preparation procedure and to the pharmaceutical compositions that contain them. These new compounds prove to be potent receptor ligands melatoninergic

Benzoxazine derivatives used as fungicides are known in the prior art (Hahn HG et al., J. Korean Chem. Soc., 1994, 38 (10), pages 776-81) or as inhibitors of mammalian lipogenesis ( US 4308276).

Numerous derivatives are also known. (dihydro) chromene 5-HT ligands useful for the treatment of hypertension, depression or anxiety (WO 9426703, DE 4135474), or as receptor agonists dopaminergic (WO 9608489) useful in the treatment of diseases cardiovascular

Other derivatives (dihydro) chromene se described as melatoninergic ligands, for example in EP 0708099 and EP 0745584 or in WO 9529173, where substituted compounds are described in the aromatic part of the molecule

On the other hand, derivatives (dihydro) benzodioxine are described as antioxidants and inhibitors of lipid peroxidation (EP 624582), or because they are useful in the treatment of liver diseases (J07242655 and J07242543), or also as α-receptor blockers adrenergic agents (Dewar GH et al., Eur. J. Med. Chem. - Chim. Ther., 1983, 18 (3), pages 286-90).

Numerous studies have shown in these last ten years the capital role of melatonin (5-methoxy-N-acetyltryptamine)  in the control of circadian rhythm and endocrine functions. In addition, the receptors of the melatonin

In addition to their beneficial action on circadian rhythm disorders (J. Neurosurg. 1985, 63 , pages 321-341) and sleep (Psychopharmacology, 1990, 100 , pages 222-226), the melatoninergic system ligands have interesting pharmacological properties on the central nervous system, in particular anxiolytics and antipsychotics (Neuropharmacology of Pineal Secretions, 1990, 8 (3-4), pages 264-272) and as analgesics (Pharmacopsychiat., 1987, 20 , pages 222-223), as well as for the treatment of Parkinson's disease (J. Neurosurg. 1985, 63 , pages 321-341) and Alzheimer's (Brain Research, 1990, 528 , pages 170-174). Similarly, these compounds have been shown to have activity on some cancers (Melatonin - Clinical Perspectives, Oxford University Press, 1988, pages 164-165), on ovulation (Science 1987, 227 , pages 714-720), on diabetes ( Clinical Endocrinology, 1986, 24 , pages 359-364) and in treatments against obesity (International Journal of Eating Disorders, 1995, 20 (4), pages 443-446).

Therefore, the compounds that allow act on the melatoninergic system are for the clinician excellent medications for the treatment of pathologies related to the melatoninergic system and in particular the mentioned above.

In particular, the present invention relates to the compounds of formula (I):

one

where:

\ blacklozenge

R 1 represents a OR 4 group in which R 4 represents a hydrogen atom, a linear (C 1 -C 6) alkyl group or branched substituted or not, linear (C2-C6) alkenyl or branched substituted or not, linear (C2-C6) alkynyl branched substituted or not, aryl, linear (C 1 -C 6) arylalkyl or branched, cycloalkyl (C 3 -C 8) replaced or not or (C 3 -C 8) cycloalkyl (C 1 -C 6) alkyl linear or branched, substituted or not,

\ blacklozenge

R2 represents a hydrogen atom,

or R1 and R2, located on two adjacent carbons, together with the carbon atoms that carry them, a phenyl or phenyl group replaced,

\ blacklozenge

X represents a group CH or CH2,

\ blacklozenge

And represents an atom of oxygen,

\ blacklozenge

R 3 represents a hydrogen atom, an aryl group, linear (C 1 -C 6) arylalkyl or branched or linear (C 1 -C 6) alkyl or branched,

\ blacklozenge

n is worth 0, 1, 2, 3, 4 or 5 when R1 and R2, located on two adjacent carbons, they form, together with the carbon atoms that carry them, a group phenyl or substituted phenyl,

 or n equals 1, 2, 3, 4, or 5 when R2 represents an atom of hydrogen,

\ blacklozenge

A represents:

• a group NR 5 R 6 in which

R 6 represents a hydrogen atom or a group linear (C 1 -C 6) alkyl or branched,

R 5 represents a group

 \ uelm {Z} {\ uelm {\ dpara} {CR 7}} 

where Z represents an oxygen atom or a sulfur atom, and R 7 represents:

-

\ vtcortauna a hydrogen atom,

-

\ vtcortauna a group R 8 representing a linear or branched (C 1 -C 6) alkyl group, substituted or not, cycloalkyl (C 3 -C 8) substituted or not, cycloalkyl (C_) {3} -C 8) linear or branched (C 1 -C 6) alkyl, substituted or not, linear or branched (C 2 -C 6) alkenyl, substituted or not, alkynyl (C 2 -C 6) linear or branched, substituted or not, aryl or aryl (C 1 -C 6) linear or branched alkyl,

-

\ vtcortauna or an NR 8 R 9 group where R 9 represents a hydrogen atom or a linear or branched (C 1 -C 6) alkyl group and R 8 is such as defined above,

or a group

 \ uelm {Z} {\ uelm {\ dpara} {C-NR 8 R 9}} 

where Z, R 8 and R 9 are as defined above,

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understanding that:

-

he term "substituted" attributed to the term "phenyl" means that this group is substituted with one or several atoms of halogen or with one or several groups, identical or different, selected from OH, linear or branched (C 1 -C 6) alkoxy, linear or branched (C 1 -C 6) alkyl, cyano, nitro, amino, alkylamino, dialkylamino or trihaloalkyl,

-

he term "substituted" attributed to the terms "alkyl", "alkenyl" and "alkynyl" means that this group is substituted with one or several halogen atoms, or with one or several groups, identical or different, selected from OH, linear or branched (C 1 -C 6) alkoxy, amino, alkylamino or dialkylamino,

-

he term "substituted" attributed to the terms "cycloalkyl" and "cycloalkylalkyl" means that the cyclic part is substituted with one or several halogen atoms or one or more groups, identical or different, selected from linear or branched (C 1 -C 6) alkyl, linear or branched (C 1 -C 6) alkoxy, hydroxyl, oxo, amino, alkylamino or dialkylamino,

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understanding that:

-

when the compound of formula (I) is a chroman derivative (X represents a group CH 2, Y represents an oxygen atom and R 1, R 2 and R3 are as defined above), then the group - (CH 2) n -A is different from those following groups:

\ text {*}

CH2 -NHCOR_e (R_ {e} representing a cycloalkyl group) at position 2 of the chroman core,

\ text {*}

CH 2 -CONHR_ {f} (R_ {f} representing a benzyl group or 1-phenyl-2-hydroxyethyl) in position 4 of the chroman core,

-

when A represents an NHCSNHR 8 group and n is worth 2, then R 8 does not can represent an aryl group,

-

when X represents a group CH2, R1 is as defined above and R2 represents a hydrogen atom, then A cannot represent a urea or thiourea group substituted with a phenyl core (substituted or not),

its enantiomers and diastereoisomers, as well as their addition salts of an acid or a pharmaceutically based acceptable.

Among the pharmaceutically acceptable acids are may cite, by way of non-limitation, hydrochloric acids, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, Tartaric, maleic, citric, ascorbic, methanesulfonic, canphoric, etc.

Among the pharmaceutically acceptable bases are may cite, without limitation, sodium hydroxide, hydroxide of potassium, triethylamine, tert-butylamine, etc.

Preferred compounds of the invention are those compounds of formula (I) in which:

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R1 and R2 located on two adjacent carbons form, together with the atoms of carbon bearing them, a phenyl or phenyl group replaced,

\ blacklozenge

R 3 represents a hydrogen atom,

\ blacklozenge

R 3 represents a aryl group,

\ blacklozenge

A represents a group of formula NR 5 R 6.

More specifically, the present invention is refers to dihydrobenzochromen and dihydrochromen derivatives.

Even more specifically, the present invention refers to those compounds of formula (I) that are:

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N- (9-methoxy-2,3-dihydro-1 H -benzo [f] chromen-2-yl) acetamide

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N- [2- (6-Methoxy-3,4-dihydro-2 H -chromenyl) ethyl] acetamide

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N - [(6-methoxy-2 H -3-chromenyl) methyl] butanoamide.

Isomers, as well as the addition salts of a pharmaceutically acceptable acid or base of the Preferred compounds of the invention form an integral part of the same.

The invention also extends to preparation process of the compounds of formula (I), characterized in that the starting product is used as compound of formula (II):

2

where R1, R 2, R 3, X and Y are as defined above and n ' can take values from 0 to 4,

which is submitted:

\ blacklozenge

to a reducing agent, to lead to the compound of formula (III):

3

where R1, R 2, R 3, X, Y and n 'are as defined previously,

being able to compounds of formula (III) on the other hand be obtained

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-

by reduction of the compound of formula (IV):

4

where R1, R 2, R 3, X, Y and n are as defined previously,

-

or to from the compound of formula (V):

5

where R1, R 2, R 3, X, Y and n are as defined above and Hal represents a halogen atom,

which is replaces with a phthalimide group and then undergoes a hydrazinolysis,

compound formula (III) on which it condenses:

-

O well a ClCOR 8 acyl chloride or acid anhydride (mixed or symmetric) corresponding, R8 being as defined previously,

  to drive to the compound of formula (I / a), particular case of the compounds of formula (I):

6

where R1, R 2, R 3, R 8, X, Y and n are as defined previously,

What can be subjected to a thionation agent such as Lawesson's reagent to obtain the compound of formula (I / b), particular case of compounds of formula (I):

7

where R1, R 2, R 3, R 8, X, Y and n are as defined previously,

-

O well a compound of formula (VI):

(VI) Z = C = N-R 8

where Z and R 8 are as defined above,

with the purpose of obtain the compound of formula (I / c), particular case of compounds of formula (I):

8

in which R 1, R 2, R 3, R 8, X, Y, Z and n are as they have been defined above,

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the set of the compounds of formulas (I / a), (I / b) and (I / c) form the compound of formula (I / d), particular case of the compounds of formula (I):

9

where R1, R 2, R 3, X, Y and n are as defined above and G represents a group COR 8, CSR 8 or CZNHR 8, where Z and R 8 as defined above,

which can be rent according to classic alkylation techniques thanks to a compound of formula (VII):

(VII) Alk - W

where Alk represents a (C 1 -C 6) alkyl group linear or branched and W represents a leaving group such as a halogen atom or a tosyl group,

or thanks to a dialkylsulfate,

to drive to compound of formula (I / e), particular case of the compounds of formula (I):

10

where R1, R 2, R 3, X, Y, G, Alk and n are as defined previously,

\ blacklozenge

or to a hydrolysis in acidic or basic medium to lead to the compound of formula (VIII):

eleven

where R1, R 2, R 3, X, Y and n 'are as defined previously,

who submits, after activation in the form of acid chloride or in the presence of a coupling agent, to the action of an amine H 2 NR 8 where R 8 is as defined previously,

to drive to compound of formula (I / f), particular case of the compounds of formula (I):

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12

where R1, R 2, R 3, R 8, X, Y and n 'are as defined previously,

What can be subjected to a thionation agent such as Lawesson's reagent to obtain the compound (I / g), particular case of the compounds of formula (I):

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13

where R1, R 2, R 3, R 8, X, Y and n 'are as defined previously,

forming the set of compounds (I / f) and (I / g) the compound of formula (I / h):

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14

where R1, R 2, R 3, R 8, X, Y, Z and n 'are as defined previously,

What can be rented according to classical alkylation techniques, to lead to compound of formula (I / i):

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fifteen

where R1, R 2, R 3, R 8, X, Y, Z, Alk and n 'are as they have been defined above,

forming the compounds of formulas (I / a) to (I / i) the set of compounds of formula (I); which they can be purified according to classical separation techniques; that they are transformed, if desired, into their acid addition salts or of a pharmaceutically acceptable base; and from which they separate eventually its isomers according to classical techniques of separation.

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The compounds of formula (II) are obtained, among others:

?

from the compounds of formula (IX):

16

where R1 and R2 are as defined above and X 'represents a sulfur or oxygen atom,

that condenses on acrylonitrile to lead to the compound of formula (II / a), particular case of the compounds of formula (II):

17

where R1, R2 and X 'are as defined above,

which is undergoes a reduction, to obtain the compound of formula (II / b), particular case of the compounds of formula (II):

18

where R1, R2 and X 'are as defined above,

?

from the compounds of formula (X):

19

where R1, R2 and X 'are as defined above,

that undergo a Wittig reaction and then a catalytic reduction to obtain the compound of formula (II / c), particular case of compounds of formula (II):

twenty

where R1, R2 and X 'are as defined above and p equals 0, 1, 2, 3, or 4,

?

from the compounds of formula (XI):

twenty-one

where R1, R2, X and Y are as defined above,

over which condenses:

*

chloroacrylonitrile to obtain the compound of formula (II / d), particular case of the compounds of formula (II):

22

where R1, R2, X and Y are as defined above,

which can dibromate and then be treated with sodium iodide to lead to compound of formula (II / e), particular case of the compounds of formula (II):

2. 3

where R1, R2, X and Y are as defined above,

*

or Ethyl 2,3-dibromopropionate, to lead to compound of formula (XII):

24

where R1, R2, X and Y are as defined above,

compound (XII) that undergoes a lithiation and then the condensation of the desired electrophile, in order to lead to the compound of formula (XV):

25

where R1, R 2, R 3, X and Y are as defined previously,

which can successively reduce to the corresponding alcohol, oxidize to aldehyde, and undergo a Wittig reaction, to lead to compound of formula (XVI):

       \ vskip1.000000 \ baselineskip
    

26

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where R1, R 2, R 3, X and Y are as defined above and q equals 0, 1, 2 or 3,

that is reduced catalytically to lead to the compound of formula (II / f), case Particular of the compounds of formula (II):

       \ vskip1.000000 \ baselineskip
    

27

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where R1, R 2, R 3, X, Y and n 'are as defined previously.

The compounds of the invention and the pharmaceutical compositions containing them prove to be useful in the treatment of disorders of the melatoninergic system.

Indeed, pharmacological studies of the derivatives of the invention have shown that they were not toxic, that they had a very high selective affinity for melatonin receptors and that they had an important activity on the central nervous system and, in particular, have revealed to possess therapeutic properties in reference to sleep disorders, anxiolytic, antipsychotic, analgesic, as well as microcirculation properties, which allows establishing that the products of the invention are useful in the treatment of stress, sleep disorders, anxiety, seasonal depressions, cardiovascular diseases, insomnia and fatigue due to time lags, schizophrenia, panic attacks, melancholy, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders related to normal aging or pathological, migraines, memory losses ia, Alzheimer's disease, as well as cerebral circulation disorders. In another area of activity, it turns out that, in the treatment, the products of the invention have ovulation inhibitory properties, such as immunomodulators and are likely to be used in the treatment of
Cancer.

Preferably, the compounds will be used in the treatment of seasonal depressions, sleep disorders, cardiovascular diseases, insomnia and fatigue due to lags schedules, appetite disorders and obesity.

For example, the compounds will be used in the treatment of seasonal depressions and disorders of the dream.

The present invention also has Subject the pharmaceutical compositions containing the products of formula (I), in combination with one or more excipients pharmaceutically acceptable.

Among the pharmaceutical compositions according to invention, may be cited, more particularly, those that are suitable for oral, parenteral, nasal, per o transcutaneous, rectal, perlingual, ocular or respiratory and particularly simple or dragee tablets, sublingual tablets, sachets, blisters, capsules, tablets soluble, tablets, suppositories, creams, ointments, dermal gels and drinkable or injectable ampoules.

The dosage varies by sex, age and patient weight, route of administration, the nature of the therapeutic indication or of possibly associated treatments and It ranges between 0.01 mg and 1 g every 24 hours, in one or several doses.

The following examples illustrate the invention, but they do not limit it in any way.

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Preparation 2

9-methoxy-3 H -benzo [f] chromen-2-carbonitrile

Phase TO

2,7-dimethoxynaphthalene

The methylation of 2,7-dihydroxynaphthalene (10 g, 62.43 mmol) is performed in the acetone (100 ml) in the presence of dimethylsulfate (12.06 ml, 127 mmol, 2.03 eq) and dry potassium carbonate (42.3 g, 306 mmol, 4.9 eq). The temperature of the reaction medium is 56 ° C for 6 hours and then 40 ° C for 12 hours. Hydrolysis  (7.4 ml of water) needs 2 hours of stirring at temperature ambient. After filtration of the salts on celite and residual filtrate concentration, dichloromethane extraction leads to an organic phase that, evaporated, takes on the appearance of a solid beige. The latter is discolored with activated carbon and then recrystallized in an EP / CH 2 Cl 2 mixture.

Melting point : 138 ° C.

Phase B

2,7-dimethoxy-1-naphthalenedehyde

To a solution of the derivative obtained in Phase A (5 g, 26.3 mmol) in anhydrous dichloromethane (50 ml) was added successively titanium tetrachloride (4.09 ml, 37.5 mmol, 1.4 eq) and α, α-dichloromethyl methyl ether (3.6 ml, 37.5 mmol, 1.5 eq) previously dissolved in 14 ml of dichloromethane. These operations were performed at 0 ° C, the temperature was taken from again gradually at 25 ° C and then kept so for 5 hours. The reaction mixture was then slowly poured onto ice, then adding a solution of 3N hydrochloric acid (103 ml) with caution. After complex hydrolysis, the product was extracted with dichloromethane, washed with water and then with a saturated solution of sodium bicarbonate. Dry residue collected after concentration was washed with diethyl ether, thus allowing to isolate the pure aldehyde.

Melting point : 94 ° C.

Phase C

2-hydroxy-7-methoxy-1-naphthalenedehyde

To the dimethoxylated product obtained in Phase B (2 g, 9.25 mmol) in solution in anhydrous dichloromethane was added the 97% BBr 3 Me 2 S complex (2.98 g, 9.25 mmol, 1 eq) at room temperature. After 35 minutes of stirring, it took carried out a hydrolysis with the help of a saturated solution of baking soda (pH = 8). The product was extracted with dichloromethane and then purified on AcOEt / EP silica column (3/7).

Melting point : 126 ° C.

Phase D

9-methoxy-3 H -benzo [f] chromen-2-carbonitrile

Under an anhydrous atmosphere, the aldehyde obtained in Phase C (2 g, 9.9 mmol) was partially solubilized in acrylonitrile (6.5 ml, 49.4 mmol, 10 eq). The solution became clear after contributing 1,4-diazabicyclo [2.2.2] octane (227 mg, 2.47 mmol, 0.25 eq). The latter was colored red during a reflux for 18 hours. The reaction medium was then diluted in ethyl acetate, washed successively with a solution of 1N sodium hydroxide (20 ml) and then with an acid solution 1N hydrochloric (20 ml). The concentrated organic phases are purified on flash silica column eluted with an AcOEt / mixture EP (0,1 / 1).

Melting point : 134 ° C.

Preparation eleven

6-methoxy-2 H -3-chromencarbonitrile

A solution of 0.61 g (4 mmol) of 2-hydroxy-5-methoxybenzaldehyde and 0.112 g (1 mmol) of 1,4-diazabicyclo [2.2.2] octane in 18 ml of acrylonitrile was refluxed for 24 hours under argon. After cooling, the medium was diluted with chloroform and then washed with a saturated sodium bicarbonate solution. The phase organic was then acidified with an acid solution hydrochloric (1N) and then the aqueous phase was extracted with chloroform. The organic phases were dried over magnesium sulfate and then filtered, concentrated under reduced pressure. Nitrile title was obtained pure in the form of a yellow solid after passing through the silica column (eluent: AcOEt / EP: 25/75).

Melting point : 70-71 ° C.

Preparation 14

9-methoxy-2,3-dihydro-1 H -benzo [f] chromen-1-one

Phase TO

3- (7-methoxy-1,4-dihydro-2-naphthalenyl) oxy] propanonitrile

We proceeded as in Phase A of Example 12 a start from 7-methoxy-1,4-dihydro-2-naphthaleneol.

Phase B

9-methoxy-2,3-dihydro-1 H -benzo [f] chromen-1-one

We proceeded as in Phases B and C of the Example 12.

Preparation fifteen

9-methoxy-2,3-dihydro-1 H -benzo [f] chromen-1-carbonitrile

In anhydrous medium, they were mixed in 20 ml of THF the ketone obtained in Preparation 14 (500 mg, 2.19 mmol), diethylcyanophosphonate (2 eq; 4.38 mmol, 715 µl) and cyanide 0.5M lithium in DMF solution (3 eq, 6.57 mmol, 13.15 ml). After 30 minutes of stirring, the reaction medium was hydrolyzed, then It was extracted with AcOEt. In parallel, a solution of samarium iodide. Samarium (4.5 eq, 9.86 mmol, 1.48 g) was placed suspended in 10 ml of THF, then, drop by drop, was added diiodoethane (3 eq; 6.57 mmol; 1.85 g) diluted in 10 ml of THF. When the samarium iodide solution turned blue, the complex formed above was dissolved in 5 ml of THF and then added 0.21 ml of tert-butanol. The solution is left under stirring for 12 hours at room temperature. He reaction medium was hydrolyzed with a 10% HCl solution. After extraction with AcOEt, the organic phase was washed with a 10% Na 2 S 2 O 3 solution, then twice with a saturated solution of NaHCO3. The residue obtained is purified by flash chromatography on silica gel (eluent: EP / AcOEt (8/2)). The title product was obtained in Shape of an oil.

Preparation 16

2- (9-methoxy-2,3-dihydro-1 H -benzo [f] chromen-1-yl) acetonitrile

Phase TO

2- (9-methoxy-2,3-dihydro-1 H -benzo [f] chromen-1-ylidene) acetonitrile

In anhydrous medium, it was added slowly diethylcyanomethylphosphonate (3 eq; 17.1 mmol; 2.76 ml) at 50% sodium hydride suspension (3 eq; 17.1 mmol; 820 mg) in 50 ml of THF, at 0 ° C. The reaction medium was stirred for 10 minutes at 0 ° C then cooled to -78 ° C. The ketone obtained was added in Preparation 14 (1.3 g; 5.7 mmol) in solution in 15 ml of THF. The temperature was brought back then, slowly, to 20-25 ° C for 2 h 30 min. After removing the solvent, the compound was extracted with AcOEt. The organic phase is washed thoroughly with a saturated NaCl solution, then concentrated under reduced pressure. The desired product was obtained in the form of a solid.

Melting point : 61-63 ° C.

Phase B

2- (9-methoxy-2,3-dihydro-1H-benzo [f] chromen-1-yl) acetonitrile

The unsaturated compound obtained in Phase A (1,775 eq; 7.07 mmol), solubilized in 50 ml of ethanol and some drops of THF, was introduced into a Parr reactor. Then it was added 10% Pd / C (266 mg; 15% by mass). It was left under a pressure of 45 psi hydrogen, under stirring, for 18 hours. After filtration on celite, the solvent was removed under pressure reduced The residue was purified by flash chromatography. on silica gel (eluent: EP / AcOEt (9/1)). The desired product It was obtained as a solid.

Melting point : 122-123 ° C.

Example 4 N - [(9-methoxy-2,3-dihydro-1 H -benzo [f] chromen-2-yl) methyl] acetamide

Phase TO

9-methoxy-2,3-dihydro-1 H -benzo [f] chromen-2-carbonitrile

200 mg (0.93 mmol) of the product obtained in the Preparation 2 were introduced into a Parr apparatus of the hydrogenator  with 15 ml of ethanol and 20 mg of 10% Pd / C. The mixture was stirred under hydrogen atmosphere for 24 h. Leaked on celite and then the ethanol was evaporated. The title product was purified on a column. of silica (eluent: EP / AcOEt, 1/1).

Phase B

N - [(9-methoxy-2,3-dihydro-1 H -benzo [f] chromen-2-yl) methyl] acetamide

175 mg of the product obtained in Phase A is dissolved in 10 ml of distilled ether. To this solution were added  77 mg of LiAlH4. The reaction was left at room temperature for 24 hours. ambient. The mixture was then hydrolyzed with 0.08 ml of water, 0.08 ml of 15% NaOH and finally 0.25 ml of water. Leaked on Celite, washed with ethyl acetate, which was evaporated. The product of the title was purified on a silica column (eluent: CH 2 Cl 2 / MeOH: 90/10).

The product was dissolved in a flask previously obtained in 5 ml of CH 2 Cl 2. They were added, at 0 ° C on ice, 0.2 ml of pyridine and 0.2 ml of acetic anhydride. It was allowed to act for 2 h. The product was then hydrolyzed and It was then extracted with dichloromethane. The organic phase was concentrated. dried over MgSO4 and then the rest of the evaporated with toluene Pyridine The title product was purified on silica column.  (eluent: CH2Cl2 / MeOH), then recrystallized from ethanol and cyclohexane.

Melting point : 138 ° C.

Elemental Microanalysis :

C H N % Calculated 71.56 6.71 4.91 % Found 71.50 6.79 4.86

Example 5 N- (9-methoxy-2,3-dihydro-1 H -benzo [f] chromen-2-yl) acetamide

Phase TO

Acid 9-methoxy-3H-benzo [f] chromen-2-carboxylic

A mixture of the cyano derivative obtained in the Preparation 2 (1 g, 4.21 mmol) and of a hydroxide solution 10% sodium (34 ml, 84.3 mmol, 20 eq) was refluxed for 5 hours. The cooled reaction medium was extracted at basic pH with ethyl acetate. The precipitation of the acid was carried out cold, by acidification of the residual aqueous phase with 2N hydrochloric acid and then 3N. The solid collected by filtration was dried under vacuum in presence of phosphorus pentoxide.

Melting point : 226 ° C.

Phase B

Acid 9-methoxy-2,3-dihydro-1H-benzo [f] chromen-2-carboxylic

The unsaturated acid obtained in Phase A (750 mg, 2.9 mmol) was solubilized in an ethanol / dimethylformamide mixture (20 ml: 3 ml) in the Paar apparatus reactor. After contributing the catalyst, 10% Pd / C (75 mg, 10% by mass), the whole is stirred at room temperature under a pressure of 45 psi for 4 hours. The solvents were removed and then the residual oil was precipitated and washed with diethyl ether.

Melting point : 165 ° C.

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Phase C

N- (9-methoxy-2,3-dihydro-1H-benzo [f] chromen-2-yl) acetamide

To the acid obtained in Phase B (50 mg, 0.19 mmol) in solution in acetone (2 ml) under an inert atmosphere, he added successively and slowly, at 0 ° C, distilled triethylamine (0.07 ml, 0.52 mmol, 2.7 eq), distilled ethyl chloroformate (0.06 ml, 0.68 mmol, 3.5 eq). After 30 minutes of stirring, it was added sodium nitride (57 mg, 0.87 mmol, 4.5 eq) in solution in 1 ml of Water. After a similar period of time, the reaction medium It was extracted with dichloromethane. The resulting organic phase is concentrated, recovered in 1 ml of toluene and refluxed for 30 minutes Glacial acetic acid was then introduced (1 ml) hot and then the heating was prolonged for 1 h 30 min. At room temperature, the products were extracted with ethyl acetate and then purified on silica column snapshot CHCl_ {3} / AcOEt 7/3. The title compound was washed with diethyl ether.

Melting point : 186 ° C.

Elemental Microanalysis :

C H N % Calculated 70.83 6.32 5.16 % Found 70.75 6.29 4.95

Example 6 N - [(9-methoxy-2,3-dihydro-1 H -benzo [f] chromen-2-yl) methyl] -2-cyclopropylacetamide

The title compound was obtained by it. procedure than for Example 4 replacing in the last stage acetic anhydride by cyclopropanoic anhydride.

Example 7 N - [(9-methoxy-2,3-dihydro-1 H -benzo [f] chromen-2-yl) methyl] -1-cyclohexylcarboxamide

The title example was obtained as in the Example 5, using cyclohexanoic acid instead of acid acetic.

Example 8 N-methyl-9-methoxy-2,3-dihydro-1 H -benzo [f] chromen-2-carboxamide

Methylamine, condensed on acid obtained in Phase B of Example 5, allowed to obtain the compound of the title.

Example 10 N- [2- (3,4-dihydro-2 H -4-chromenyl) ethyl] acetamide

Phase TO

2- (3,4-dihydro-2H-4-chromeniliden) acetonitrile

The diethyl cyanomethylphosphonate (1.15 eq) is slowly added to a suspension of sodium hydride (1.15 eq) in anhydrous tetrahydrofuran at 0 ° C. The reaction medium was stirred. for 10 minutes at 0 ° C and then refrigerated at -78 ° C. Was added 4-Chromanone solution in tetrahydrofuran. The temperature was brought back then slowly to 20-25 ° C for 2 h 30 min. After removing the solvent, the compounds were extracted with ethyl acetate. The organic phase was washed thoroughly with a saturated solution of sodium chloride. This last concentration was purified on a column. of silica (AcOEt / EP 3/7) (Z / E mixture).

Phase B

2- (3,4-dihydro-2H-4-chromenyl) acetonitrile

The unsaturated compound obtained in Phase A (Z + E mixture) solubilized in ethanol (20 ml) was introduced into the Parr apparatus reactor. 10% Pd / C was then added (in mass). The double bond was hydrogenated at a pressure of 45 psi during 12 hours.

The catalyst was removed by filtration and then the solvent was evaporated. The residual oil was purified on a column of silica eluted with an AcOEt / EP 3/7 mixture.

Colorless oil

       \ global \ parskip1.000000 \ baselineskip
    

Phase C

N- [2- (3,4-dihydro-2H-4-chromenyl) ethyl] acetamide

The saturated cyano derivative obtained in Phase B it was solubilized in the reactor of the Parr apparatus with anhydride acetic. Then, acetate acetate was introduced into the reaction medium sodium (1.5 eq) and Raney nickel (6 mg per 50 mg of product). He whole was heated at 50 ° C under a hydrogen pressure of 40 psi for 12 hours The solvent was removed after return to normal temperature and pressure conditions, the extraction is performed by means of ethyl acetate. A purification by flash chromatography (CHCl3 / AcOEt 7/3) of the organic phase Concentrated led to the sought amide.

Colorless rubber

Example 11 N- [2- (3,4-dihydro-2 H -4-chromenyl) ethyl] ethanethioacetamide

The compound obtained in Example 10 submitted the Lawesson reagent allowed to obtain the compound of Title.

Example 12 N- [2- (6-Methoxy-3,4-dihydro-2 H -4-chromenyl) ethyl] acetamide

Phase TO

2- (4-methoxyphenoxy) cyanoethane

A mixture of 4-methoxyphenol (10 g, 80.5 mmol) and triton B (2.29 ml, 14.5 mmol, 0.18 eq) in Acrylonitrile (50 ml) was refluxed for 48 hours. He solvent was partially removed, the products were extracted with ethyl acetate, washed with water and then with a solution of 6N hydrochloric acid. The residual brown oil was purified in a flash silica column eluted with a gradient of AcOEt / EP.

Melting point : 58 ° C (pale yellow solid).

Phase B

3- (4-Methoxyphenoxy) propanoic acid

Hydrolysis of the cyano derivative obtained in the Phase A (3 g, 16.93 mmol) was performed with the help of hydrochloric acid 37% concentrate (8.3 ml, 84.3 mmol, 5 eq) at reflux. After the solution of the starting product, the desired compound is precipitated after 2 hours of heating. Reaction medium cooled, the solid was filtered, washed with a mixture of ice-water, was introduced in a solution of 10 ml of water containing 1 g of sodium bicarbonate. The latter stirred vividly for 1 hour and then filtered. The resulting filtering led to pure acid after cold acidification (acid 3N hydrochloric) and filtration.

Melting point : 104 ° C (white solid).

Phase C

6-methoxy-4-chromanone

Cyclization was performed on the chloride of acid generated from acid. The reflux heating of toluene (20 ml) of the acid obtained in Phase B (500 mg, 2.55 mmol) for 3 hours in the presence of thionyl chloride (0.56 ml, 7.65 mmol, 3 eq) allowed the latter to be easily accessed. Solvent and excess reagent was removed by concentration under pressure reduced yellow solution obtained. Dry residue it was then recovered in 20 ml of anhydrous dichloromethane and then cautiously introduced aluminum chloride (465.9 mg, 3.49 mmol, 1.5 eq). The reaction mixture was cold hydrolyzed after 1 stirring time at room temperature. The product was extracted, it was washed with water and then purified by a silica column (AcOEt / EP 3/7).

Melting point : 43 ° C (pale yellow solid).

Phase D

2- (6-methoxy-3,4-dihydro-2H-4-chloromeniliden) acetonitrile

We proceeded as in Phase A of Example 10 a from the compound obtained in Phase C.

Phase AND

2- (6-methoxy-3,4-dihydro-2H-4-chromenyl) acetonitrile

We proceeded as in Phase B of Example 10 a from the compound obtained in Phase D.

Colorless oil

Phase F

N- [2- (6-Methoxy-3,4-dihydro-2H-4-chromenyl) ethyl] acetamide

We proceeded as in Phase C of Example 10 a from the compound obtained in Phase E.

Melting point : 138 ° C.

Elemental Microanalysis :

C H N % Calculated 67.45 7.68 5.62 % Found 66.90 7.74 5.49

Example 13 N- [2- (6-Methoxy-3,4-dihydro-2 H -4-chromenyl) ethyl] butanamide

The cyano derivative (500 mg; 2.46 mmol) obtained in Phase E of Example 12 it was solubilized in the Parr reactor with methanol (50 ml). Raney nickel (6 mg per 50 mg was then added of product). The mixture was heated at 50 ° C under a pressure of 40 psi hydrogen for 16 hours. Nickel leaked then on celite and the methanol evaporated. The raw mix it was dissolved in anhydrous dichloromethane (10 ml), then the solution was refrigerated at 0 ° C. Butyryl Chloride (1.4 eq; 3.36 mmol; 348 mul) and then triethylamine (3 eq; 7.2 mmol; 1.013 was added ml) to medium. After an hour of stirring, the mixture of The reaction was acidified with a solution of hydrochloric acid (1N). After extraction with dichloromethane, the organic phase was washed with a saturated sodium bicarbonate solution, dried over magnesium sulfate and then concentrated in vacuo. The residue obtained was purified by flash chromatography having as eluent EP / AcOEt (6/4), then (1/1) and then (4/6).

The product was obtained as crystals white after washing with ether and pentane.

Melting point : 63-64 ° C.

Elemental Microanalysis :

C H N % Calculated 69.29 8.36 5.05 % Found 69.30 8.31 5.05

Example 15 N- [2- (6-Methoxy-3,4-dihydro-2 H -4-chromenyl) ethyl] -2-phenylacetamide

We proceeded as in Phases A, B, C, D and E of Example 12, then a reduction of nitrile was performed under the Conditions of Phase C of Example 1, then a condensation of the phenylacetyl chloride allowed to obtain the compound of Title.

Example 36 N - [(6-methoxy-3,4-dihydro-2 H -3-chromenyl) methyl] acetamide

0.935 g (5 mmol) of the nitrile obtained in the Preparation 11 and 0.623 g (7.5 mmol) of sodium acetate were added  to a suspension of 0.44 g of Raney nickel in 20 ml of anhydride acetic and then the mixture was subjected to a pressure of 50 psi of hydrogen at a temperature of 50 ° C for 24 hours. After cooling, the salts were filtered and then the solvent was evaporated under vacuum. The obtained residue was recovered in acetate ethyl and then the organic phase was washed with a saturated solution of baking soda. After drying over sulfate Magnesium and filtration, the filtrate was concentrated in vacuo. A silica column chromatography (eluent: AcOEt) allowed lead to the title amide in the form of a white solid.

Melting point : 110 ° C.

Elemental Microanalysis :

C H N % Calculated 66.36 7.28 5.95 % Found 66.54 7.40 5.90

Example 37 N - [(6-methoxy-3,4-dihydro-2 H -3-chromenyl) methyl] -1-cyclobutanecarboxamide

We proceeded as in Phase B of Example 4 a starting from the compound obtained in Preparation 11, and then condensed cyclobutanoic anhydride to lead to the compound of Title.

Example 38 N- [2- (6-methoxy-3,4-dihydro-2 H -3-chromenyl) ethyl] acetamide

Phase TO

(6-methoxy-3,4-dihydro-2H-3-chromenyl) methanol

2 g (10.5 mmol) of the alcohol obtained in the Preparation 12 was dissolved in 60 ml of ethanol and then added 0.616 g (10.5 mmol) of previously washed Raney nickel in ethanol to this solution. The reaction medium was subjected to a 50 psi hydrogen pressure for 22 hours. Catalyst The residual was filtered and then the solvent was evaporated in vacuo. A silica column chromatography (eluent: AcOEt / EP: 50/50) allowed to lead to pure title alcohol in the form of a solid White.

Melting point : 56-57 ° C.

Phase B

[(6-Methoxy-3,4-dihydro-2H-3-chromenyl) methyl] 4-methyl-1-benzenesulfonate

1.83 g (9.44 mmol) of the alcohol obtained in Phase A was dissolved in 40 ml of anhydrous dichloromethane, then 3.15 g (16.5 mmol) of para- toluenesulfonyl chloride and 4.6 ml were added (33 mmol) of triethylamine successively in the medium. After 21 hours of stirring at room temperature and under argon, the solvent was evaporated under reduced pressure. The title tosylate was obtained pure in the form of a clear oil after passing through a silica column (eluent: AcOEt / EP: 15/85 and then 30/70).

Phase C

2- (6-methoxy-3,4-dihydro-2H-3-chromenyl) acetonitrile

1.6 g (4.56 mmol) of the tosylate obtained in Phase B was dissolved in 25 ml of anhydrous N, N-dimethylformamide and then 0.724 g (11.5 mmol) of potassium cyanide were added to the solution. After 4 hours of reflux under argon, the solvent was evaporated in vacuo and then the residue was recovered with a saturated sodium bicarbonate solution. The aqueous phase was then extracted with dichloromethane. The organic phases were dried over magnesium sulfate and then filtered, concentrated under reduced pressure. The nitrile of the title was obtained pure in the form of an oil that crystallizes slowly after chromatography on silica gel (eluent: AcOEt / EP:
25/75).

Melting point : 54-55 ° C.

Phase D

N- [2- (6-methoxy-3,4-dihydro-2H-3-chromenyl) ethyl] acetamide

0.812 g (4 mmol) of nitrile was added obtained in Phase C at a suspension of 0.35 g (6 mmol) of nickel of Raney and 0.5 g (6 mmol) of sodium acetate in 40 ml of anhydride acetic. The reaction medium was then subjected to a pressure of 50 psi hydrogen at a temperature of 50 ° C for 5 hours. After cooling the medium, the salts were filtered and the Filtrate was concentrated under reduced pressure. The residue obtained is then recovered with ethyl acetate and then the organic phase washed with a saturated sodium bicarbonate solution. After drying over magnesium sulfate and filtration, the solvent was evaporated in vacuo. A column chromatography of silica (eluent: AcOEt) allowed to lead to the title amide in Shape of a white solid.

Melting point : 114 ° C

Elemental Microanalysis :

C H N % Calculated 67.45 7.68 5.62 % Found 67.72 7.71 5.62

Example 39 N-methyl-N-phenyl-2- (6-methoxy-3,4-dihydro-2 H -3-chromenyl) acetamide

The title compound was obtained after hydrolysis of nitrile obtained in Phase C of Example 38, transformation into the corresponding acid chloride and condensation of the N-methyl-N-phenylamine.

Example 46 N - [(6-methoxy-3,4-dihydro-2 H -4-chromenyl) methyl] acetamide

Phase TO

6-methoxy-4-chromancarbonitrile

In anhydrous medium, the compound was mixed obtained in Phase C of Example 12 (500 mg; 2.8 mmol), diethylcyanophosphonate (2 eq; 8.4 mmol; 16.8 ml) in 25 ml of THF. After 30 minutes of stirring, the reaction medium is hydrolyzed and then extracted with AcOEt. In parallel, a Samarium iodide solution. Samarium (4.5 eq; 12.6 mmol; 1.9 g) was suspended in 15 ml of THF and then added dropwise to drop diiodoethane (3 eq; 8.4 mmol; 2.37 g), diluted in 15 ml of THF. When the solution of samarium iodide turned blue, the complex formed above was dissolved in 5 ml of THF and 0.3 ml of tert-butanol, then added to this solution of SmI_ {2}. The solution was left under stirring for 12 hours at room temperature.

The reaction medium was hydrolyzed with a 10% HCl solution. After extraction with AcOEt, the phase Organic was washed with a solution of Na 2 S 2 O 3 at 10%, then twice with a saturated NaHCO3 solution.

The obtained residue was purified by flash chromatography on silica gel (eluent: EP / AcOEt (8/2)). The title product was obtained as an oil.

Phase B

N - [(6-methoxy-3,4-dihydro-2H-4-chromenyl) methyl] acetamide

Nitrile obtained in Phase A (200 mg; 1.05 mmol) was solubilized in the Parr apparatus reactor in 15 ml of acetic anhydride. Raney nickel (60 mg; 30% by mass) was added and sodium acetate (1.5 eq; 1.58 mmol; 130 mg). He placed the reactor under a hydrogen pressure of 580 psi, at 50 ° C, for 12 hours. When the reaction was over, it was filtered over celite and then cleared with AcOEt. The product was purified by chromatography. "flash" on silica gel (eluent: AcOEt (100%)). Solid White obtained was recrystallized from a pentane-ether mixture.

Melting point : 140-141 ° C.

Elemental Microanalysis :

C H N % Calculated 66.36 7.28 5.95 % Found 66.43 7.40 5.95

Example 47 N - [(6-methoxy-3,4-dihydro-2 H -4-chromenyl) methyl] butanamide

In anhydrous medium at 0 ° C, the nitrile obtained in Phase A of Example 46 (500 mg; 2.64 mmol) was solubilized in 5 ml of ether and then LiAlH4 (126 mg; 5.5 was gradually added mmol; 2.1 eq). The mixture was refluxed for 2 hours. The hydrolysis of the reaction medium was performed with 130 µl of water, 130 µl of a 15% NaOH solution and then with 370 µl of water. The salts were filtered on sintered, rinsed with CH 2 Cl 2 and then the solvents were removed under pressure reduced The amine thus obtained (300 mg; 1.53 mmol) was dissolved in 6 ml of CH 2 Cl 2 at 0 ° C. Triethylamine (3 eq; 4.59 was added mmol; 640 µl) and butyryl chloride (1.4 eq; 2.14 mmol; 222 \ mul). It was left under stirring at room temperature for 5 hours. After evaporation of the solvent, the product was extracted with CH 2 Cl 2. The residue was purified by chromatography. "flash" on silica gel (eluent: AcOEt / EP (1/1)). He Title product was obtained in the form of an oil.

Elemental Microanalysis :

C H N % Calculated 68.41 8.04 5.32 % Found 68.42 8.23 5.15

Example 48 N- [2- (6-Methoxy-3,4-dihydro-2 H -4-chromenyl) ethyl] -3-butenamide

In anhydrous medium, the nitrile obtained in Phase E of Example 12 (740 mg; 3.64 mmol) was solubilized in 30 ml of ether and then LiAlH 4 (1.5 eq; 5.46 mmol; 207 mg) was added a little at little bit. It was left 3 hours at reflux under argon. After return to room temperature, 210 µl of water were successively added, 210 µL of a 15% NaOH solution and then 620 µL of Water. The solution was left 30 minutes at room temperature under agitation. The salts were filtered over sintered, the filtrate was dried over MgSO4 and evaporated under reduced pressure. Oil Yellow color obtained was used directly in the stage next: in anhydrous medium, at -10 ° C, acid 3-butenoic acid (1.5 eq; 5.43 mmol; 467 mg) and HOBT (1.5 eq; 5.43 mmol; 733 mg) It was left under stirring, under argon at -10 ° C for 30 minutes In parallel, the amine was dissolved in 10 ml of CH 2 Cl 2 was distilled off and placed in the presence of triethylamine (1 eq; 3.62 mmol; 504 µl). Then the acid was added 3-butenoic "activated" to the amine solution free. The reaction medium was left 2 hours at -10 ° C and then 60 hours at room temperature. The mixture was then washed and of successively with 1N HCl, water, 1N NaOH, water, dried over MgSO4 and the solvent was evaporated under reduced pressure. The residue  obtained was purified by flash chromatography on gel silica (eluent: EP / AcOEt (3/7)). The product was obtained in form of white crystals after washing with ether.

Melting point : 73-74 ° C.

Elemental Microanalysis :

C H N % Calculated 69.79 7.69 5.09 % Found 69.57 7.67 5.17

Example 50 N - [(6-methoxy-3,4-dihydro-2 H -3-chromenyl) methyl] butanamide

Phase TO

6-methoxy-3-chromancarbonitrile

0.9 g (4.8 mmol) of the nitrile obtained in the Preparation 11 was added to a suspension of 0.09 g of Pd / C in 15 ml of anhydrous methanol and then the mixture was subjected to a hydrogen pressure of 50 psi for 22 hours. After filtration of the residual catalyst, the solvent was evaporated at vacuum and then the reaction crude was purified on silica column (eluent: petroleum ether / ethyl acetate 75/25) to drive to the nitrile of the title in the form of a white solid.

Melting point : 79-80 ° C.

Phase B

(6-methoxy-3,4-dihydro-2H-3-chromenyl) methylamine

0.51 g (2.7 mmol) of nitrile were reduced obtained in Phase A with lithium aluminum hydride in the bosom of ether to lead to the title amine in the form of A yellow oil.

Phase C

N - [(6-methoxy-3,4-dihydro-2H-3-chromenyl) methyl] butanamide

A solution of 0.4 g (2.06 mmol) of the amine obtained in Phase B in 20 ml of anhydrous dichloromethane was refrigerated  at 0 ° C. To the medium was added successively 1 ml (7.2 mmol) of triethylamine and 0.38 g (3.6 mmol) of butyryl chloride. After one hour of stirring under argon, the reaction mixture was acidified with a 1N hydrochloric acid solution, then the aqueous phase is extracted with dichloromethane. The organic phase was dried over sulfate of magnesium and then concentrated in vacuo. The title amide is obtained pure in the form of a white solid after its passage through the silica column (eluent: petroleum ether / ethyl acetate 50/50).

Melting point : 110-111 ° C.

Elemental Microanalysis :

C H N % Calculated 68.41 8.04 5.32 % Found 68.59 8.13 5.39

Example 51 N- [2- (9-Methoxy-2,3-dihydro-1 H -benzo [f] chromen-1-yl) ethyl] acetamide

The nitrile obtained in Preparation 16 (400 mg; 1.58 mmol) was solubilized in the Parr reactor in 22 ml of acetic anhydride. Raney nickel (60 mg; 30% by mass) was added and sodium acetate (1.5 eq; 2.37 mmol; 208 mg). The reactor was placed under a hydrogen pressure of 50 psi. After 12 hours of reaction at 50 ° C, the reaction mixture was filtered over celite and then it was rinsed with CH 2 Cl 2. The different solvents are evaporated and then the residue was hydrolyzed and extracted with AcOEt. He product was purified by flash chromatography on gel silica (eluent: AcOEt (100%) and then AcOEt / MeOH (95/5)). Solid it was obtained after recrystallizing from ether containing some Isopropanol drops

Melting point : 106-107 ° C.

Elemental Microanalysis :

C H N % Calculated 72.21 7.07 4.68 % Found 71.81 7.22 4.70

Example 52 N- [2- (9-methoxy-2,3-dihydro-1 H -benzo [f] chromen-1-yl) ethyl] butanamide

In anhydrous medium and at 0 ° C, the nitrile obtained in Preparation 16 (200 mg; 0.79 mmol) was solubilized in 5 ml of ether and then LiAlH 4 (2.1 eq; 1.66 mmol; 63 mg was added ) slowly. The mixture was refluxed for 2 hours. The hydrolysis of the medium was carried out with 64 µl of water, 64 µl of a 15% NaOH solution and then with 190 µl of water. The salts were filtered over sintered, rinsed with ether and the solvents removed under reduced pressure. The amine thus obtained (0.79 mmol) was dissolved in 2 ml of CH2Cl2 at 0 ° C. Triethylamine (3 eq; 1.87 mmol; 260 µl) and butyryl chloride (1.4 eq; 1.11 mmol; 115 µl) was added. It was left under stirring at room temperature for 2 hours. After evaporation of the solvent, the product was extracted with CH2Cl2. The residue was purified by flash chromatography on silica gel (eluent: CH 2 Cl 2 (100%) and then CH 2 Cl 2 / MeOH (95/5)). The title product was obtained as a solid after recrystallization from an Et 2 O / EtOH mixture.
(8/2).

Melting point : 114 ° C.

Elemental Microanalysis :

C H N % Calculated 73.36 7.70 4.28 % Found 73.00 7.56 4.18

Example 53 N- [2- (9-Methoxy-2,3-dihydro-1 H -benzo [f] chromen-1-yl) methyl] acetamide

The nitrile obtained in Preparation 15 (200 mg; 0.84 mmol) was solubilized in the Parr reactor in 15 ml of acetic anhydride. Raney nickel (60 mg; 30% by mass) and sodium acetate (3 eq; 2.52 mmol; 200 mg) was added. The reactor was placed under a hydrogen pressure of 50 psi. After 12 hours of reaction at 50 ° C, the reaction mixture was filtered over celite and then rinsed with CH 2 Cl 2. The different solvents were evaporated and then the residue was hydrolyzed and extracted with AcOEt. The product was purified by flash chromatography on silica gel (eluent: CH2Cl2 / MeOH (95/5)). The title compound was obtained as a solid after washing with
ether.

Melting point : 145-147 ° C.

Elemental Microanalysis :

C H N % Calculated 71.55 6.71 4.91 % Found 71.84 6.66 5.04

Example 54 N- [2- (9-methoxy-2,3-dihydro-1 H -benzo [f] chromen-1-yl) methyl] butanamide

In anhydrous medium and at 0 ° C, the nitrile obtained in Preparation 15 (300 mg; 1.25 mmol) was solubilized in 5 ml of ether, then LiAlH 4 (3 eq; 3.75 mmol; 143 mg) was added a little at little bit. The mixture was refluxed for 3 hours. Hydrolysis of the medium was done with 220 µl of water, 64 µl of a 15% NaOH solution and then with 650 µl of water. Salts filtered on sintered, rinsed with CH2Cl2 and then the solvents were removed under reduced pressure. The amine thus obtained (300 mg; 1.53 mmol) was dissolved in 6 ml of CH 2 Cl 2 at 0 ° C. Triethylamine (3 eq; 3.76 mmol; 254 was added µl) and butyryl chloride (1.4 eq; 1.76 mmol; 183 µl). Be left under stirring at room temperature for 5 hours. After evaporation of the solvent, the product was extracted with CH 2 Cl 2. The residue was purified by chromatography. "flash" on silica gel (eluent: AcOEt / EP (7/3)). He title product was obtained in the form of a colored solid white after crystallization from ether.

Melting point : 118-119 ° C.

Elemental Microanalysis :

C H N % Calculated 72.81 7.40 4.47 % Found 72.49 7.40 4.71

Pharmacological study Example A Acute toxicity study

Acute toxicity was studied after oral administration to groups of 8 mice (26 ± 2 grams). The animals were observed at regular intervals over the course of the first day and daily during the two weeks following the treatment. The DL 50 was evaluated, which causes the death of 50% of the animals, demonstrating the low toxicity of most compounds of the invention.

Example B Melatonin receptor binding study 1) Study on cells of the pars tuberalis of the ram

Melatonin receptor binding studies of the compounds of the invention were carried out according to classical techniques, on ram pars tuberalis cells. In mammals, the pars tuberalis of the adenohypophysis is characterized, in fact, by a high density of melatonin receptors (Journal of Neuroendocrinology, 1 , pages 1-4, 1989).

Protocol

one)

Ram pars tuberalis membranes were prepared and used as white tissue in saturation assays to determine binding capacities and affinities for 2 - [125 I] -iodomelatonin.

2)

The Ram pars tuberalis membranes were used as tissue blank with the different compounds to be tested in binding assays competitive in relation to melatonin.

Each trial was performed in triplicate and was tested a range of different concentrations for each compound. The results allow to determine, after statistical treatment, the binding affinities of the compound rehearsed

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Results

It turns out that the compounds of the invention have a strong affinity for the receptors of the melatonin

2) Study on chicken brain homogenate membranes ( Gallus domesticus )

The animals used were chickens ( Gallus domesticus ) 12 days old. They sacrificed between 1pm and 5pm on the day of their arrival. Brains were quickly removed and frozen at -200 ° C, then kept at -80 ° C. The membranes were prepared according to the method described by Yuan and Pang (Journal of Endocrinology, 128 , pages 475-482, 1991). 2 - [125 I] -iodomelatonin was incubated in the presence of the membranes in a buffer solution at pH 7.4 for 60 min at 25 ° C. At the beginning of this period, the membrane suspension (Whatman GF / C) was filtered. The radioactivity retained on the filter was determined using a Beckman® LS 6000 liquid scintillation counter.

The products used were:

-

2 - [125 I] -iodomelatonin

-

melatonin

-

usual products

-

original molecules.

In a first investigation, the molecules are tested at 2 concentrations (10-7 and 10-5M). Each result is the average of 3 independent measures. The active molecules retained after screening results primary were subject to a quantitative determination of their efficiency (IC 50). These were used at 10 concentrations different.

Thus, the IC_ {50} values found for the preferred compounds of the invention demonstrate that the binding of the compounds tested is very potent.

Example C Four plate test

The products of the invention were administered Esophageal route to groups of ten mice. A group received syrup from rubber. Thirty minutes after the administration of the products to study, the animals were placed in rooms whose floor It comprised four metal plates. Every time the animal went from One plate to another received a slight electrical discharge (0.35 mA). The number of steps was recorded for one minute. After the administration, the compounds of the invention increased so significant the number of steps, which demonstrates the activity Anxiolytic derivatives of the invention.

Example D Action of the compounds of the invention on the rhythms circadians of locomotive activity in the rat

The involvement of melatonin in the day / night alternation training of most rhythms physiological, biochemical and behavioral circadians have allowed to establish a pharmacological model for the search of melatoninergic ligands.

The effects of the molecules were subjected to test in reference to numerous parameters and, in particular, about circadian rhythms of locomotive activity, which they represent a reliable marker of circadian clock activity endogenous.

In this study the effects of such molecules on a particular experimental model, namely: the rat placed in temporary isolation (permanent darkness).

Experimental protocol

1 month old Long Evans male rats since they arrived at the laboratory a luminous cycle of 12 h of light for 24 h (L / D 12:12).

After 2 to 3 weeks of adaptation, it placed in cages equipped with a wheel connected to a system of registration in order to detect the phases of locomotive activity and thus follow circadian rhythms.

Once the recorded rhythms testify a stable workout by the light cycle L / D 12:12, the rats they went into permanent darkness (D / D).

Two to three weeks later, when the free course (rhythm that reflects that of the endogenous clock) is clearly established, the rats receive a daily administration of the molecule to be tested

The observations were made by visualization of activity rhythms:

-

activity rhythm training by the light / dark (L / D) cycle,

-

disappearance of the training of rhythms in permanent darkness, activity training by daily administration of the molecule; transient effect or long lasting.

A computer program allows:

-

to size the duration and intensity of the activity, the rhythm time in animals in free course and during treatment,

-

evidence eventually, by analysis spectral, the existence of circadian components and not circadians (ultradians for example).

Results

It turns out clearly that the compounds of the invention allow to act potently on the circadian rhythm through the melatoninergic system.

Example E Antiarrhythmic activity Protocol

(Ref .: LAWSON JW et al. J. Pharmacol. Expert. Therap., 1968, 160 , pages 22-31).

The substance to be tested was administered via intraperitoneal to a group of 3 mice 30 minutes before exposure to anesthesia with chloroform. The animals were then observed for 15 min. The absence of registration of arrhythmias and heart rates greater than 200 beats / min (control: 400-480 beats / min) in two animals at less indicates significant protection.

Example F Pharmaceutical composition: tablets

\dotl

5 g1,000 tablets dosed with 5 mg of N- (9-methoxy-2,3-dihydro-1 H -benzo [f] chromen-2-yl) {} • acetamide (Example 5)

 \ dotl 

5 g

\dotl

20 gWheat starch

 \ dotl 

20 g

\dotl

20 gCornstarch

 \ dotl 

20 g

\dotl

30 gLactose

 \ dotl 

30 g

\dotl

2 gMagnesium stearate

 \ dotl 

2 g

\dotl

1 gSilica

 \ dotl 

1 g

\dotl

2 gHydroxypropyl cellulose

 \ dotl 

2 g

Claims (13)

1. Compound of formula (I):

         \ vskip1.000000 \ baselineskip
      

28

         \ vskip1.000000 \ baselineskip
      

where:

\ blacklozenge

R 1 represents a OR 4 group in which R 4 represents a hydrogen atom, a linear (C 1 -C 6) alkyl group or branched substituted or not, linear (C2-C6) alkenyl or branched substituted or not, linear (C2-C6) alkynyl branched substituted or not, aryl, linear (C 1 -C 6) arylalkyl or branched, cycloalkyl (C 3 -C 8) replaced or not or (C 3 -C 8) cycloalkyl (C 1 -C 6) alkyl linear or branched, substituted or not,

\ blacklozenge

R2 represents a hydrogen atom,

or R1 and R2, located on two adjacent carbons, together with the carbon atoms that carry them, a phenyl or phenyl group replaced,

\ blacklozenge

X represents a group CH or CH2,

\ blacklozenge

And represents an atom of oxygen,

\ blacklozenge

R 3 represents a hydrogen atom, an aryl group, linear (C 1 -C 6) arylalkyl or branched or linear (C 1 -C 6) alkyl or branched,

\ blacklozenge

n is worth 0, 1, 2, 3, 4 or 5 when R1 and R2, located on two adjacent carbons, they form, together with the carbon atoms that carry them, a group phenyl or substituted phenyl,

or n equals 1, 2, 3, 4, or 5 when R2 represents an atom of hydrogen,

\ blacklozenge

A represents:

• a group NR 5 R 6 in which

R 6 represents a hydrogen atom or a group linear (C 1 -C 6) alkyl or branched,

R 5 represents a group

 \ uelm {Z} {\ uelm {\ dpara} {CR 7}} 

where Z represents an oxygen atom or a sulfur atom, and R 7 represents:

-

\ vtcortauna a hydrogen atom,

-

\ vtcortauna a group R 8 representing a linear or branched (C 1 -C 6) alkyl group, substituted or not, cycloalkyl (C 3 -C 8) substituted or not, cycloalkyl (C_) {3} -C 8) linear or branched (C 1 -C 6) alkyl, substituted or not, linear or branched (C 2 -C 6) alkenyl, substituted or not, alkynyl (C 2 -C 6) linear or branched, substituted or not, aryl or aryl (C 1 -C 6) linear or branched alkyl,

-

\ vtcortauna or an NR 8 R 9 group where R 9 represents a hydrogen atom or a linear or branched (C 1 -C 6) alkyl group and R 8 is such as defined above,

or a group

 \ uelm {Z} {\ uelm {\ dpara} {C-NR 8 R 9}} 

where Z, R 8 and R 9 are as defined above,

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understanding that:

-

he term "substituted" attributed to the term "phenyl" means that this group is substituted with one or several atoms of halogen or with one or several groups, identical or different, selected from OH, linear or branched (C 1 -C 6) alkoxy, linear or branched (C 1 -C 6) alkyl, cyano, nitro, amino, alkylamino, dialkylamino or trihaloalkyl,

-

he term "substituted" attributed to the terms "alkyl", "alkenyl" and "alkynyl" means that this group is substituted with one or several halogen atoms, or with one or several groups, identical or different, selected from OH, linear or branched (C 1 -C 6) alkoxy, amino, alkylamino or dialkylamino,

-

he term "substituted" attributed to the terms "cycloalkyl" and "cycloalkylalkyl" means that the cyclic part is substituted with one or several halogen atoms or one or more groups, identical or different, selected from linear or branched (C 1 -C 6) alkyl, linear or branched (C 1 -C 6) alkoxy, hydroxyl, oxo, amino, alkylamino or dialkylamino,

         \ vskip1.000000 \ baselineskip
      

understanding that:

-

when the compound of formula (I) is a chroman derivative (X represents a group CH 2, Y represents an oxygen atom and R 1, R 2 and R3 are as defined above), then the group   - (CH 2) n -A is different from those following groups:

*

CH2 -NHCOR_e (R_ {e} representing a cycloalkyl group) at position 2 of the chroman core,

*

CH 2 -CONHR_ {f} (R_ {f} representing a benzyl group or 1-phenyl-2-hydroxyethyl) in position 4 of the chroman core,

-

when A represents an NHCSNHR 8 group and n is worth 2, then R 8 does not can represent an aryl group,

-

when X represents a group CH2, R1 is as defined above and R2 represents a hydrogen atom, then A cannot represent a urea or thiourea group substituted with a phenyl core (substituted or not),

its enantiomers and diastereoisomers, as well as their addition salts of an acid or a pharmaceutically based acceptable. 2. Compounds of formula (I) according to claim 1, wherein R 1 and R 2 located on two adjacent carbons form, together with the carbon atoms that they carry, a phenyl or substituted phenyl group, their enantiomers and diastereoisomers, as well as their addition salts of an acid or a pharmaceutically acceptable base. 3. Compounds of formula (I) according to claim 1, wherein R 1 represents an OR 4 group, its enantiomers and diastereoisomers, as well as their addition salts of a pharmaceutically acceptable acid or base. 4. Compounds of formula (I) according to the claim 1, wherein R 3 represents a hydrogen atom, their enantiomers and diastereoisomers, as well as their addition salts of a pharmaceutically acceptable acid or base. 5. Compounds of formula (I) according to the claim 1, wherein R 3 represents an aryl group, its enantiomers and diastereoisomers, as well as their addition salts of a pharmaceutically acceptable acid or base. 6. Compounds of formula (I) according to the claim 1, wherein A represents a group of formula NR 5 R 6, its enantiomers and diastereoisomers, as well as its addition salts of a pharmaceutically acidic or base acceptable. 7. Compounds of formula (I) according to claim 1 which are dihydrobenzochromenos or dihydrochromen, their  enantiomers and diastereoisomers, as well as their addition salts of a pharmaceutically acceptable acid or base. 8. Compound of formula (I) according to claim 1 which is N- (9-methoxy-2,3-dihydro-1 H -benzo [f] chromen-2-yl) acetamide, its enantiomers and diastereoisomers, as well as their Addition salts of a pharmaceutically acceptable acid or base. 9. Compound of formula (I) according to claim 1 which is N- [2- (6-methoxy-3,4-dihydro-2 H -chromenyl) ethyl] acetamide, its enantiomers and diastereoisomers, as well as their addition salts of a pharmaceutically acceptable acid or base. 10. Compound of formula (I) according to claim 1 which is N - [(6-methoxy-2 H -3-chromenyl) methyl] butanamide, its enantiomers and diastereoisomers, as well as its addition salts of an acid or a base pharmaceutically acceptable.

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11. Method of preparing the compounds of formula (I) according to claim 1, characterized in that a compound of formula (II) is taken as the starting product: 29

where R1, R 2, R 3, X and Y are as defined above and n ' can take values from 0 to 4,

which is submit:

         \ vskip1.000000 \ baselineskip
      

\ blacklozenge

to a reducing agent, to lead to the compound of formula (III):

30

where R1, R 2, R 3, X, Y and n 'are as defined previously,

being able to compounds of formula (III) on the other hand be obtained

         \ vskip1.000000 \ baselineskip
      

-

by reduction of the compound of formula (IV):

31

where R1, R 2, R 3, X, Y and n are as defined previously,

         \ vskip1.000000 \ baselineskip
      

-

or to from the compound of formula (V):

32

where R1, R 2, R 3, X, Y and n are as defined above and Hal represents a halogen atom,

which is replaces with a phthalimide group and then undergoes a hydrazinolysis,

compound formula (III) on which it condenses:

-

O well a ClCOR 8 acyl chloride or acid anhydride (mixed or symmetric) corresponding, R8 being as defined previously,

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         \ global \ parskip0.900000 \ baselineskip
      

to drive to compound of formula (I / a), particular case of the compounds of formula (I):

33

where R1, R 2, R 3, R 8, X, Y and n are as defined previously,

What can be subjected to a thionation agent such as Lawesson's reagent to obtain the compound of formula (I / b), particular case of compounds of formula (I):

3. 4

where R1, R 2, R 3, R 8, X, Y and n are as defined previously,

-

O well a compound of formula (VI):

(VI) Z = C = N-R 8

where Z and R 8 are as defined above,

with the purpose of obtain the compound of formula (I / c), particular case of compounds of formula (I):

35

in which R 1, R 2, R 3, R 8, X, Y, Z and n are as they have been defined above,

the set of the compounds of formulas (I / a), (I / b) and (I / c) form the compound of formula (I / d), particular case of the compounds of formula (I):

36

where R1, R 2, R 3, X, Y and n are as defined above and G represents a group COR 8, CSR 8 or CZNHR 8, where Z and R 8 as defined above,

which can be rent according to classic alkylation techniques thanks to a compound of formula (VII):

(VII) Alk - W

where Alk represents a (C 1 -C 6) alkyl group linear or branched and W represents a leaving group such as a halogen atom or a tosyl group,

         \ global \ parskip1.000000 \ baselineskip
      

or thanks to a dialkylsulfate,

to drive to compound of formula (I / e), particular case of the compounds of formula (I):

         \ vskip1.000000 \ baselineskip
      

37

where R1, R 2, R 3, X, Y, G, Alk and n are as defined previously,

\ blacklozenge

or to a hydrolysis in acidic or basic medium to lead to the compound of formula (VIII):

         \ vskip1.000000 \ baselineskip
      

38

where R1, R 2, R 3, X, Y and n 'are as defined previously,

who submits, after activation in the form of acid chloride or in the presence of a coupling agent, to the action of an amine H 2 NR 8 where R 8 is as defined previously,

to drive to compound of formula (I / f), particular case of the compounds of formula (I):

         \ vskip1.000000 \ baselineskip
      

39

where R1, R 2, R 3, R 8, X, Y and n 'are as defined previously,

What can be subjected to a thionation agent such as Lawesson's reagent to obtain the compound (I / g), particular case of the compounds of formula (I):

         \ vskip1.000000 \ baselineskip
      

40

where R1, R 2, R 3, R 8, X, Y and n 'are as defined previously,

         \ newpage
      

forming the set of compounds (I / f) and (I / g) the compound of formula (I / h):

41

where R1, R 2, R 3, R 8, X, Y, Z and n 'are as defined previously,

What can be rented according to classical alkylation techniques, to lead to compound of formula (I / i):

42

where R1, R 2, R 3, R 8, X, Y, Z, Alk and n 'are as they have been defined above,

forming the compounds of formulas (I / a) to (I / i) the set of compounds of formula (I); which can be purified according to techniques classical separation; that become, if desired, in their addition salts of a pharmaceutically acidic or base acceptable; and from which their isomers eventually separate according to classical separation techniques.

12. Pharmaceutical compositions containing as active ingredient at least one of the compounds of formula (I) according to any one of claims 1 to 10 or one of its addition salts with a pharmaceutically based acid or base acceptable in combination with one or more excipients pharmaceutically acceptable. 13. Pharmaceutical compositions according to claim 12 useful for the treatment of disorders of the melatoninergic system